Potent androgen deprivation therapy has been achieved with the recently FDA approved inhibitors enzalutamide and abiraterone acetate resulting in significant survival benefits for men with prostate cancer. However, the prolonged clinical use of potent inhibitors of androgen receptor signaling may also be yielding resistance phenotypes including treatment related neuroendocrine prostate or t-NE CaP. This resistance phenotype may be, in turn, a cause for the increasing trend of aggressive, soft tissue metastasis that continues to be observed in the clinic. This hypothesis remains controversial and requires rigorous pre-clinical modeling to evaluate whether complete suppression of androgen receptor signaling remains beneficial or whether it is leading to an aggressive, neuroendocrine phenotype in patients. Our long-term goal is to ascertain when and how much androgen receptor inhibition is necessary to prevent prostate cancer progression while preventing the development of resistance phenotypes. We aim to obtain prognostic data sets to identify patients that are genetically predisposed to developing t- NECaP as well as signatures that may facilitate treatment for patients who have acquired t-NE CaP. The objective is to provide treatment and genetic based evidence that potent androgen receptor signaling blockade is a cause of t-NECaP, develop preclinical models recapitulating key genetic alterations found in human NE CaP cohorts and determine a potential cell(s) of origin for treatment induced NE CaP. Our central hypothesis is that suppression of the androgen receptor signaling pathway leads to neuroendocrine prostate cancer through trans differentiation of stem-progenitor cells. We will test these hypotheses and address this clinical problem by the following interrelated Specific Aims: 1. Establish the impact of chronic androgen deprivation treatment on neuroendocrine prostate cancer progression. We will apply therapies and genetic techniques in collaboration with novel reporter assays to determine the impact of potent suppression of androgen receptor signaling on NE CaP phenotypes. 2. Determine if REST is a critical genetic switch that cooperates with ENZA to promote NE CaP. Using genetically engineered mouse models we will model the frequent loss of REST, observed in human NE CaP cohorts, for potential to reprogram prostate epithelium to a neuroendocrine lineage. We will cross reference molecular signatures from our models with clinical data sets for NE CaP. 3. Evaluate the potential for therapy-induced accumulation of NE CaP through trans differentiation of stem/progenitor cells. We will determine whether prostate epithelium with known stem- progenitor qualities can initiate a process of therapy driven trans differentiation towards NE CaP phenotype.